Psoriasis is a disease that affects millions of Americans with chronic recurrent exacerbations and remissions that are emotionally and physically debilitating. Several treatments are available, but in many cases these are inadequate. This application is based on the premise that topical administration of prodrugs should result in high concentrations of the active drug at the lesion site with lower concentrations systemically. Less total dose could be used than with oral administration. The efficacy of the drug might be maintained at this lower dose; thus, topical prodrugs might lead to safer products. We propose to design, synthesize and test topical prodrugs of some of the effective systemic drugs for psoriasis, plus some compounds whose potential efficacy is predicted from a biochemial understanding of psoriasis. There is a substantial volume of literature on the pathophysiology of psoriasis and the therapeutic potential of lipoxygenase inhibitors. Since there is no animal model for psoriasis, the biological testing will be done with the arachidonic acid mouse ear model designed to test lipoxygenase inhibitors. If this Phase I project is successful, pharmacological, toxicological, and clinical studies will be proposed for promising candidate prodrugs.